Introduction

Irritable bowel syndrome (IBS) has a worldwide prevalence of ~11%, and thus has a considerable negative impact on both society and millions of individuals. The pathophysiology of IBS is multifactorial and incompletely understood, involving low-grade inflammation in the gut, visceral hypersensitivity, increased epithelial barrier permeability, altered gut-brain interactions, and an unfavourable composition of gut microbiota. Although we currently have no cure for IBS, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) has shown to give ~70% of patients clinically significant symptom relief.

Aims & Methods

In this study, we seek to uncover how 12 weeks of strict low-FODMAP diet affect the intestinal immune system, visceral hypersensitivity, and gut integrity in patients with IBS. We will use highly multiplexed Hyperion imaging mass cytometry to investigate the cellular microenvironments in duodenal biopsies from n = 48 patients and n = 21 healthy controls at baseline and n = 21 patients at 12-week follow-up.

Results

With basis in known literature on relevant markers in IBS, we have developed an antibody panel for use on formalin-fixed, paraffin-embedded (FFPE) duodenal tissue with Hyperion imaging mass cytometry. The panel includes 35 markers for comprehensive spatial analyses of the gut mucosa in IBS before and after diet intervention. It comprises several immune cell markers for a broad immunologic mapping, in addition to markers for gut integrity and neuro-immune communication. The panel was tested on duodenal FFPE tissue with Hyperion, and resulting images were segmented with the Steinbock framework. Downstream single-cell analysis was performed in R with the imcRtools R/Bioconductor and cytomapper packages. Different cell types, including CD4 and CD8 T cells, were identified in duodenal tissue by means of cell segmentation and unsupervised clustering.

Conclusion

Through multimodal integration of tissue analyses and clinical symptom scores before and after treatment, we aim to provide clinically meaningful intestinal biomarkers in order to improve treatment strategies for patients with IBS.

Introduction

Recent societal guidelines suggest there is no role for hydrogen and methane breath testing (HMBT) to exclude small intestinal bacterial overgrowth (SIBO) in patients with diarrhoea predominant irritable bowel syndrome (IBS) and to treat symptoms with rifaximin empirically^1,2. However, a positive result for SIBO with lactulose HMBT has been shown to predict more favourable outcomes to rifaximin in patients with diarrhoea predominant IBS³. We wanted to investigate if symptoms and medical history can predict lactulose HMBT outcome hence justifying treatment of SIBO without a formal diagnosis.

Aims & Methods

A large questionnaire-based study was conducted in over 1000 patients of which 731 completed lactulose HMBT. The 26-item questionnaire included questions about medical history, symptoms, and pattern of symptoms, and we used this to identify any positive predictors for SIBO on HMBT. A positive lactulose HMBT was determined by a rise of ≥20 ppm in breath hydrogen from baseline within 90 minutes³. Breath samples were analysed using gas chromatography. Associations and predictors were calculated using chi square tests and logistic regression, respectively.

Results

Bloating (93.6%), abdominal pain (87.3%), and diarrhoea (80.3%) were the most common symptoms reported by those with a positive result for SIBO, but their duration, frequency and onset were no different to patients with a negative result (P > 0.05). There were no positive predictors for SIBO on lactulose HMBT based on symptoms, medications or medical history except for chronic low ferritin (P = 0.025).

Conclusion

This large questionnaire study has demonstrated that symptoms and medical history cannot predict HMBT outcomes for SIBO. Therefore, treatment of SIBO without a diagnosis confirmed on HMBT may lead to unnecessary antibiotic use and costs.

References

1. Vasant DH, Paine PA, Black CJ, Houghton LA, Everitt HA, Corsetti M, Agrawal A, Aziz I, Farmer AD, Eugenicos MP, Moss-Morris R, Yiannakou Y, Ford AC. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut. 2021 Jul;70(7):1214-1240.
2. Savarino E, Zingone F, Barberio B, Marasco G, Akyuz F, Akpinar H, Barboi O, Bodini G, Bor S, Chiarioni G, Cristian G, Corsetti M, Di Sabatino A, Dimitriu AM, Drug V, Dumitrascu DL, Ford AC, Hauser G, Nakov R, Patel N, Pohl D, Sfarti C, Serra J, Simrén M, Suciu A, Tack J, Toruner M, Walters J, Cremon C, Barbara G. Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility. United European Gastroenterol J. 2022 Jul;10(6):556-584.
3. Rezaie A, Heimanson Z, McCallum R, Pimentel M. Lactulose Breath Testing as a Predictor of Response to Rifaximin in Patients With Irritable Bowel Syndrome With Diarrhea. Am J Gastroenterol. 2019 Dec;114(12):1886-1893.

Introduction

This report presents the results of a multicenter, randomized, double-blind, placebo-controlled phase 3 study (VP-VLY-686-3301) assessing the efficacy of tradipitant in relieving symptoms of gastroparesis. Tradipitant, a novel NK-1 receptor antagonist, previously demonstrated efficacy in diabetic and idiopathic gastroparesis in reducing gastroparesis symptoms in a phase 2 study (VP-VLY-686-2301).

Aims & Methods

N=201 idiopathic and diabetic gastroparesis patients with delayed gastric emptying, moderate to severe nausea, and at least 1 vomiting episode were included in the ITT (Intent-to-Treat) population. Subjects were randomized to receive 85 mg tradipitant twice a day (n=102) or placebo (n=99) for 12 weeks. Nausea was assessed daily using the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptom improvement was evaluated using the Patient Global Impression of Change (PGI-C) and the Overall Patient Benefit (OPB) scales. Sensitivity analyses were also performed to control for confounders that may have masked the true treatment effect size.

Results

At the primary endpoint of change in nausea from baseline as measured by the GCSDD at week 12, both tradipitant and placebo showed significant and similar reductions from baseline at 1.55 and 1.49 respectively. Comparison between treatment arms did not reach statistical significance in this measure. However, in the PGI-C scale, more tradipitant treated patients demonstrated response as compared to placebo both at week 2 (74% v. 58%, p=0.019) and at week 12 (78% v. 66%, p=0.065). Similarly, in the OPB scale, more tradipitant treated patients demonstrated response as compared to placebo both at week 2 (81% v. 62%, p=0.0003) and week 12 (86% v. 71%, p=0.011).
Sensitivity analysis adjusting for rescue medication use further confirmed the ITT findings in both the PGI-C and OPB analysis at both week 2 and week 12.

Conclusion

Significant but similar improvements from baseline for tradipitant and placebo may have masked the true treatment effect size at the primary endpoint of the study of change in nausea severity as measured by daily diary at week 12 leading to no statistically significant difference between treatments. Despite this large placebo effect, tradipitant was shown to be significantly better than placebo in global measures of patient improvement including the Patient Global Impression of Change (PGI-C) and the Overall Patient Benefit (OPB) scales.

Disclosure

Study was sponsored by Vanda Pharmaceuticals, Inc. Authors are employees of Vanda Pharmaceuticals, Inc.